Tissue Distribution of125 l-LabeIed Albumin in Rats, and Whole Blood and Exhaled Elimination Kinetics of Octafluoropropane in Anesthetized Canines, Following Intravenous Administration of Optison® (FS069)

Abstract

OPTISON, an agent being developed as an intravenous (IV) ultrasound contrast agent, consists of a suspension of octafluoro-propane(OFP)-containing albumin microspheres. The distribution and elimination of the albumin component and the elimination kinetics of the OFP component of OPTISON (FS069) were studied in the conscious rat and anesthetized canine models, respectively. Radioiodinated OPTISON at 0.25 ml/kg (average dose 5.4 × 107 DPM/rat) and nonradioactive OPTISON, at dosages of 0.3, 0.6, and 1.0 ml/kg, was administered intravenously to conscious rats or to sodium pentobarbital-anesthetized and ventilated canines, respectively. A separate group of rats was housed in metabolism cages for 24 hours to capture excreted radioactivity. The tissue distribution data for the radiolabeled albumin in rats showed that the 125I activity recovered in the liver was the highest of all the tissues at each timepoint (peak liver radioactivity at 5 minutes with 50.4% of the dose), suggesting that the major route of uptake and metabolism of the radiolabeled albumin shell and its fragments occurred in the liver. The 125I activity was excreted in the urine, where most of the recovered radioactivity (58.3%) was found at the end of 24 hours. In the anesthetized canine study, simultaneous venous blood samples and exhaled air samples plus additional exhaled air samples were analyzed by gas chromatography. OFP was rapidly exhaled through the lungs after an IV injection such that a maximum of less than 10% of the total dose appeared in the venous blood samples. Statistical moment analysis showed rapid OFP elimination with mean residence times of 46, 41, and 38 seconds for the three dosages, and mean total recoveries for the exhaled OFP were 111%, 100.5%, and 121.6%, respectively. OFP was rapidly exhaled through the lungs after OPTISON injection with short mean residence times from statistical moment analysis. Exhaled OFP displayed one-compartment model kinetics with a measurable distribution phase in the blood using classical pharmacokinetic modeling. The albumin component appeared to be cleared primarily by the liver and radioactivity was excreted in the urine.